Ribavirin Dose Reduction
Studies have shown that adequate doses of ribavirin reduce the risk of relapse after interferon-based therapy for chronic hepatitis C. As reported in the January 2007 issue of Clinical Gastroenterology & Hepatology, K.R. Reddy and colleagues evaluated the impact of ribavirin and/or pegylated interferon dose reduction on sustained virological response (SVR) rates in patients with genotype 1 HCV. The analysis was based on pooled data from 569 participants enrolled in two Phase III trials of Pegasys plus ribavirin, of whom 427 completed treatment. They found that neither early virological response nor SVR were impaired by ribavirin dose reduction, as long as patients received a total cumulative exposure of at least 60% of the intended amount. Ribavirin dose reduction had a minimal impact on SVR in the subset of patients who achieved rapid virological response (RVR) by four weeks, even if they received less than 60% of the intended cumulative dose. However, the SVR rate was significantly lower among patients with ribavirin reductions below 60% who did not achieve RVR. The researchers concluded that “[m]inor ribavirin dose reductions to manage adverse events do not appear to affect SVR adversely, unless cumulative exposure is less than 60%.”

Treatment of Adolescents with HCV
While there have been many studies of interferon-based therapy for chronic hepatitis C in adults, there is less information about treatment of children and adolescents. In the January 2007 Journal of Clinical Gastroenterology, R.D. Baker and colleagues reported on a case series of 10 pediatric patients aged 11 to 18 years old who were treated with pegylated interferon plus ribavirin; three had previously undergone unsuccessful interferon-based therapy. Treatment continued for 48 weeks, except for one patient with genotype 3a who was treated for 24 weeks and one who did not complete therapy. All but one of the adolescents had undetectable HCV viral load at some point during or after treatment. Three achieved SVR, including one of the previous non-responders. “In response to treatment with pegylated interferon and ribavirin, children and adolescents with chronic hepatitis C achieve results similar to those seen in adults,” the researchers concluded. “Previous antiviral therapy does not preclude positive response to pegylated interferon and ribavirin.”

Monoclonal Antibody for HCVSeveral novel types of antiviral therapy for chronic hepatitis C are currently under study, including genetically engineered monoclonal antibodies. As reported in the January 2007 Journal of Hepatology, E. Galun and colleagues conducted a Phase I clinical trial to assess the safety and antiviral activity of HCV-AB68, a human monoclonal antibody against the HCV envelope protein that previously was shown to neutralize the virus in cell cultures and in a mouse model. Fifteen participants received single-dose infusions of HCV-AB68 ranging from 0.25-40 mg. In six patients, HCV viral load transiently decreased – by 2-fold to 100-fold – immediately after infusion, but rebounded to baseline levels within 24-48 hours. In addition, 25 participants received multiple doses of HCV-AB68, with 10-120 mg administered once weekly for three weeks, then three times during the fourth week. Eight patients experienced at least a 1-log reduction in HCV viral load, and 17 had at least a 0.75-log reduction at one or more time points following infusion. In both parts of the study, HCV-AB68 was well-tolerated, with no serious adverse events. The researchers concluded that these results support further investigation of HCV-AB68, including for the prevention of recurrent HCV infection in patients who received liver transplants for end-stage liver disease.

HCV and Insulin ResistanceTwo recent studies looked at insulin resistance – a condition in which cells do not respond normally to insulin, leading to impaired glucose metabolism – in people with chronic hepatitis C. In the December 2006 American Journal of Gastroenterology, N. Taura and colleagues from Japan reported on the association between liver fibrosis and impaired glucose tolerance in 83 chronic HCV-infected patients. They found that severe fibrosis was the only independent risk factor associated with insulin resistance. There were significant differences in both HOMA-IR insulin resistance scores and beta cell function (cells in the pancreas that produce insulin) between patients with mild fibrosis and those with severe fibrosis. “Our findings suggest that the development of liver fibrosis is associated with insulin resistance in HCV-infected patients,” they concluded.

In the second study, reported in the January 11, 2007 electronic edition of the American Journal of Gastroenterology, T. Kawaguchi and colleagues analyzed the effects of anti-HCV therapy and viral clearance on insulin resistance, beta-cell function, and expression of insulin receptor substrate (IRS)1/2 molecules involved in insulin signaling. They found that patients who achieved SVR to interferon-based therapy had significantly decreased HOMA-IR insulin resistance scores, improved beta cell function, and greater expression of IRS1/2 in the liver. They concluded that “clearance of HCV improves insulin resistance, beta-cell function, and hepatic IRS1/2 expression.”

IL-7 Levels and CD4 CountsSeveral studies have shown that HIV/HCV coinfected individuals experience slower or “blunted” CD4 cell recovery after starting antiretroviral therapy. As reported in the January 11, 2007 issue of AIDS, N. Soriano-Sarabia and colleagues conducted a cross-sectional study of 97 HIV positive subjects who had not previously used antiretroviral drugs (40 of whom were coinfected with HCV) and 92 antiretroviral-experienced patients (49 of whom had HCV). Both antiretroviral-naive and antiretroviral-experienced coinfected patients had significantly lower blood levels of IL-7 – a cytokine that stimulates proliferation of immune cells including B-cells and T-cells – than HIV monoinfected individuals. Subjects with lower IL-7 levels tended to have more advanced fibrosis, although the difference did not reach statistical significance. “[W]e found a correlation between IL-7 levels and the CD4 cell count in HIV/HCV coinfected patients on HAART, supporting the theory that HCV coinfection may alter IL-7 levels,” the researchers concluded. “These lower levels may explain, at least partly, the lower CD4 cell repopulation of HIV/HCV coinfected patients after HAART.”

Retreatment of Coinfected PatientsAs reported in the January 2007 Journal of Clinical Virology, M. Rodrguez-Torres and colleagues conducted a study to assess the safety and efficacy of retreatment with 180 mg/week pegylated interferon (Pegasys) plus 800 mg/day ribavirin in 41 HIV/HCV coinfected patients who were nonresponders to prior interferon-based therapy. After 24 weeks, those with at least a 2-log decrease in HCV viral load continued therapy for an additional 24 weeks, while those with poor early response stopped treatment. The overall SVR rate was 22% in an intent-to-treat analysis, or 26% counting only the 35 patients who completed at least 24 weeks of therapy. As expected, SVR was associated with improvement in liver histology and reduced fibrosis progression. However, even patients who did not achieve SVR still experienced significant decreases in histology grade and fibrosis progression rate, leading the researchers to conclude that pegylated interferon plus ribavirin conferred “histological benefits beyond virological response” that “may decrease risk of progression to end stage liver disease.”